WO2018104954A1 - Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes - Google Patents

Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes Download PDF

Info

Publication number
WO2018104954A1
WO2018104954A1 PCT/IN2017/000139 IN2017000139W WO2018104954A1 WO 2018104954 A1 WO2018104954 A1 WO 2018104954A1 IN 2017000139 W IN2017000139 W IN 2017000139W WO 2018104954 A1 WO2018104954 A1 WO 2018104954A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
phenyl
compound
reaction mixture
dimethoxyquinolin
Prior art date
Application number
PCT/IN2017/000139
Other languages
English (en)
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Gogulapati Venkata Panakala Rao
Sagyam RAJESHWAR REDDY
Gandham SHYAM KIRAN BABU
Boge RAJESHAM
Original Assignee
Msn Laboratories Private Limited, R&D Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Msn Laboratories Private Limited, R&D Center filed Critical Msn Laboratories Private Limited, R&D Center
Priority to EP17878899.8A priority Critical patent/EP3551612A4/fr
Priority to US16/467,853 priority patent/US11261160B2/en
Publication of WO2018104954A1 publication Critical patent/WO2018104954A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel crystalline forms of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula-
  • the present invention also relates to novel crystalline forms of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l -dicarboxamide hydrochloride salt compound of formula- l b.
  • Cabozantinib (S)-malate is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy.
  • Cabozantinib has been approved by the US FDA as CO ETRIQ for the treatment of patients with progressive, metastatic medullary thyroid cancer.
  • COMETRIQ has also been approved by the European Commission for the Treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.
  • Cabozantinib chemically known as N- ⁇ 4-[(6,7-dimethoxyquinolin-4-yloxy]phenyl ⁇ - N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide.
  • C 104961680 A discloses crystal A and crystal B of hydrochloride salt of Cabozantinib and process for its preparation.
  • CN 104961681 A discloses various acid addition salts of Cabozantinib and process for its preparation.
  • the first aspect of the present invention is to provide novel crystalline form of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l ! l - dicarboxamide hydrochloride salt compound of formula- lb, herein after designated as form- and process for its preparation.
  • the second aspect of the present invention is to provide an improved process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4-fluorophenyl)cyclo propane- 1 ,1 -dicarboxamide (S)-malate compound of formula-l a.
  • the third aspect of the present invention is to provide novel crystalline form of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide hydrochloride salt compound of formula- l b, herein after designated as form-S and process for its preparation.
  • the fourth aspect of the present invention is to provide novel crystalline form of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-l ,l - dicarboxamide hydrochloride salt compound of formula- l b, herein after designated as form-N and process for its preparation.
  • the fifth aspect of the present invention is to provide novel crystalline form of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , ] - dicarboxamide hydrochloride salt compound of formula- l b, herein after designated as form-R and process for its preparation.
  • the sixth aspect of the present invention is to provide novel crystalline form of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l ; l - dicarboxamide (S)-malate compound of formula- l a, herein after designated as form-M and process for its preparation.
  • the seventh aspect of the present invention is to provide novel crystalline form of N- (4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , 1 - dicarboxamide (S)-malate compound of formula- l a, herein after designated as form-S and process for its preparation.
  • the eighth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyI)-N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a.
  • Figure 1 Illustrates the PXRD pattern of crystalline form-M of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- 1 b.
  • Figure 2 Illustrates the PXRD pattern of crystalline form-S of N-(4-(6 5 7-dimethoxy quinolin- 4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l -dicarboxamide hydrochloride salt compound of formula- l b.
  • Figure 3 Illustrates the PXRD pattern of crystalline form-N of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- l b.
  • Figure 4 Illustrates the PXRD pattern of crystalline form-R of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyt)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- 1 b.
  • Figure 5 Illustrates the PXRD pattern of crystalline form-M of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a.
  • Figure 6 Illustrates the PXRD pattern of crystalline form-S of N-(4-(6,7-dimethoxyquinolin- 4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a.
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents” such as dimethoxy methane, tetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like; "ester solvents” such as methyl acetate,
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as potassium hydride, lithium hydride and the like; ammonia; and organic bases such "alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide and the like; triethyl amine, methyl amine, ethyl amine, 1 ,8-diazabicyclo [5.4.0]undec-7-ene (DBU), l ,5-di
  • the "hydrochloric acid source" used herein the present invention is selected from hydrochloric acid gas, aqueous hydrochloric acid, ethano!ic-HCI, methanolic-HCl, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether- hydrochloric acid, and trimethylchlorosilane.
  • the first aspect of the present invention provides a crystalline form-M of N-(4-(6,7- dimethoxyquinoIin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- l b, characterized by its powder x-ray diffraction pattern having peaks at 6.4, 7.8, 8.6, 9.5, 10.4, 10.8, 12.0, 12.7, 13.4, 14.7, 16.0, 1 7.2, 1 7.5, 1 8.6, 20.2, 20.8, 21 .5, 22.1 , 22.7, 23.2, 24.1 , 26.5, 26.8 and 27.2 ⁇ 0.2 degrees two theta as depicted in figure- 1 .
  • the suitable solvent is selected from chloro' solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- 1 ,1 -dicarboxamide hydrochloride salt compound of formula- l b, comprising of: ⁇
  • the second aspect of the present invention provides an improved process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclo propane- 1 ,1 -dicarboxamide (S)-malate compound of formula-la, comprising of the following steps:
  • the suitable chlorinating agent is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride;
  • the suitable base is selected from inorganic or organic base;
  • the suitable hydrochloric acid source is selected from hydrochloric acid gas, aqueous hydrochloric acid, ethyl acetate-hydrochloric acid, ethanolic- HCI, methanolic-HCl, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether-hydrochloric acid, and trimethylchlorosilane;
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures.
  • the preferred embodiment of the present invention provides an improved process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclo propane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a, comprising of the following steps:
  • the present invention have overcame the problems associated with the prior art, by simply converting the crude Cabozantinib into its acid addition salt and then treating the acid addition salt of Cabozantinib with a suitable base to provide Cabozantinib free base compound of formula- 1 with enhanced purity.
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate compound of formula- l a obtained according to the present invention is having l -((4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)carbamoyl)cyclopropane carboxylic acid ⁇ M-Acid Impurity ⁇ ; l -((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid ⁇ Acid Impurity ⁇ ; N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane- l , l -di carboxamide ⁇ Hydroxy Impurity ⁇ ; N-(4-((6,7-dimethoxyquinolin-4-yloxy)
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate compound of formula- l a obtained according to the present invention is having particle size distribution D90 ⁇ 100 ⁇ .
  • the third aspect of the present invention provides a crystalline form-S of N-(4-(6,7- dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloric acid salt compound of formula- l b, characterized by its powder x-ray di ffraction pattern having peaks at 5. 1 , 6.5, 7.9, 8.6, 9.7, 10.5, 12.8, 13.4, 1 5.2, 16.
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N' -(4- fluorophenyl)cyclopropane- l , l -dicarboxamide hydrochloride salt compound of formula- l b, comprising of the following steps:
  • the fourth aspect of the present invention provides a crystalline form-N of N-(4-(6,7- dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloric acid salt compound of formula- l b, characterized by its powder x-ray diffraction pattern having peaks at 4.0, 5.1 , 6.3, 7.5, 8.0, 8.6, 9.4, 10.5, 1 1 .2, 1 1 .8, 12.6, 1 3.3 , 1 3.5, 1 5.0.
  • In another embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N 1 -(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- 1 b, comprising of: a) Adding a suitable solvent to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt of compound of formula- l b,
  • step-a) filtering the reaction mixture and drying to get crystalline form-N of N-(4-(6,7- dimethoxyquinolin-4-yloxy)phenyl)-N '-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide hydrochloride salt compound of formula- l b.
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride salt compound of formula- l b, comprising of:
  • the fourth aspect of the present invention provides a crystalline form-R of N-(4-(6,7- dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , 1 -dicarboxamide hydrochloride salt compound of formula- l b, characterized by its powder x-ray diffraction pattern having peaks at 8.5, 9.3, 10.5, 1 1 .6, 1 1 .8, 12.1 , 12.5, 12.9, 13.2, 13.7, 14.5, 1 5.5, 16.
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof;
  • step-b) the suitable hydrochloric acid source is same as defined in step-(c) of the second aspect of the present invention.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N' -(4- fluorophenyl)cyclopropane- l , l -dicarboxamide hydrochloride salt compound of formula- l b, comprising of the following steps:
  • the crude compound of formula- 1 was treated with a suitable acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromande!ate, p-toluene sulfonic acid, ethane- 1 ,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid to provide its corresponding acid addition salt of compound of formula- 1 and further neutralizing .the acid addition salt
  • the sixth aspect of the present invention provides novel crystalline form-M of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l - dicarboxamide (S)-malate compound of formula- l a, characterized by its powder x-ray diffraction pattern having peaks at 7.0, 7.4, 7.8, 9.4, 1 1 .0, 1 1 .4, 1 1 .9, 12.6, 1 3.6, 14.0, 1 5.4, 15.6, 16.1 , 17.2, 18.4, 19.2, 19.9, 21 .1 , 21.8, 22.1 , 22.4, 23.
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof;
  • step-b) the suitable temperature is ranging from 30°C to reflux temperature of the solvent used in the reaction;
  • the suitable temperature is ranging from -50°C to 0°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4- fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a, comprising of the following steps:
  • the another preferred embodiment of the present invention provides a process for the preparation of crystalline form : M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)- '-(4- fluorophenyl)cyclopropane-l , l -dicarboxamide (S)-malate compound of formula- l a, comprising of the following steps: a) Adding n-heptane to N-(4-(6,7-dimethoxyquinolin-4-yloxy)pheny])-N'-(4-fluoro phenyl)cyclopropane- 1 , 1 -dicarboxamide compound of formula- 1 ,
  • the another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate .
  • compound of formula- l a comprising of the following steps:
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a, comprising of the following steps:
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l - dicarboxamide (S)-malate compound of formula- l a and hydrochloride salt compound of ⁇ formula-l b respectively produced according to the present invention are useful in the preparation of pharmaceutical formulation.
  • the seventh aspect of the present invention provides novel crystalline form-S of N-(4- (6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l - dicarboxamide (S)- ' ma
  • a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclo propane- 1 , 1 -dicarboxamide (S)-malate compound of formula- 1 comprising of; a) Adding a suitable solvent to crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N'-(4-iluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a,
  • step-c) adding the obtained filtrate in step-c) to a pre-cooled suitable anti-solvent at suitable temperature
  • step-b) the suitable temperature is ranging from ambient temperature to the reflux temperature of the solvent used in the reaction;
  • the suitable anti-solvent is selected from chloro solvents and hydrocarbon solvents; the suitable temperature is ranging from - 10°C to 20°C;
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixture thereof.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a. comprising of;
  • step-c) adding the obtained filtrate in step-c) to a pre-cooled dichloromethane at 0-5°C, e) stirring the reaction mixture, f) filtering the precipitated solid and drying to get crystalline form-S of N-(4-(6,7 ⁇ dimethoxyquinolin-4-y loxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -di carboxamide (S)-malate compound of formula- l a.
  • the crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N , -(4-fluoro phenyl)cyclopropane-l ,l -dicarboxamide (S)-malate compound of formula- l a obtained according to the present invention can be prepared by using crystalline form-M of compound of formula- la disclosed in the present invention or any of the free base compound of frormula-1 or compound of formula- l a known in the prior art.
  • Samples of crystalline form-S of Cabozantinib (S)-malate (3.0 gms) is subjected to heating in a vacuum dryer at 60°C for 24 hours.
  • the P-XRD pattern was results to show that crystalline form-S of Cabozantinib (S)-malate is stable.
  • the eighth aspect of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclo propane- 1 ,1 -dicarboxamide (S)-malate compound of formula- ! a, comprising of:
  • the suitable base is selected from organic or inorganic bases
  • the suitable solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixture thereof; in step-f) the suitable temperature is ranging from 30°C to reflux temperature of the solvent used; in step-h) the suitable anti-solvent, is selected from chloro solvents; in step-i) the suitable temperature is ranging from 20°C to -20°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a, comprising of:
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline forr -S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a, comprising of:
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane-l,l -dicarboxamide (S)-malate compound of formula- l a. comprising of: a) Treating N-(4-(6 ) 7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoropheny!)cyclo propane- 1 , 1 -dicarboxamide hydrochloride salt with aqueous sodium carbonate and water,
  • step-g) adding the reaction mixture obtained in step-g) to a pre-cooled solvent and stirring the reaction mixture, i) filtering the precipitated solid and dried to provide crystalline form-S of N-(4-(6,7- dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- l , l - dicarboxamide (S)-malate compound of formula- l a.
  • the suitable base is selected from organic or inorganic bases
  • the suitable solvent is selected from alcohol solvents, ester solvents, ketone solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixture thereof
  • the suitable solvent is selected from chloro solvents.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a. comprising of:
  • step-f) adding the reaction mixture obtained in step-f) to a pre-cooled dichloromethane and stirring the reaction mixture at 0-5°C,
  • the crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N '-(4-fluoro phenyl)cyclopropane- l , l -dicarboxamide (S)-malate compound of formula- l a according to the present invention is having purity greater than 99.95% by HPLC.
  • the starting materials compound of formula-2 and compound of formula-4 used in the present invention can be prepared by any of the prior known process.
  • Crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro phenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate compound of formula- l a obtained according to. the present invention is having particle size distribution D90 ⁇ 100 ⁇ .
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoropheny l)cyclopropane- 1 , 1 - dicarboxamide compound of formula- l a and formula- l b produced by the present invention can be further micronized or milled in a conventional techniques to get the .desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • compositions comprising compound of formula- l or salts thereof of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations' 1 include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-ma!ate compound of formula- l a obtained according to the present invention is having purity greater than 99.9 % by HPLC.
  • Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • the reaction mixture was slowly added to a pre-cooled mixture of 4-((6,7-dimethoxyquinolin-4-yloxy)aniline (1 00 gms), aqueous potassium carbonate solution (418.5 gms of potassium carbonate in 600 ml of water) and tetrahydrofuran (600 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate. Combined the organic layers.
  • Aqueous hydrochloric acid solution (75 ml of HCl in 725 ml of water) was added to the organic layer at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and ethyl acetate, To the obtained compound, isopropanol (22.0 Its) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 152 gms; Chloride content: 7.0%.
  • Example-2 Preparation of crystalline form-S of Cabozantinib hydrochloride salt
  • a mixture of water (840 ml) and N-(4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4- fluorophenyl) cyclopropane- l , l -dicarboxamide hydrochloride ( 120 gms) was stirred for 10 minutes at 25-30°C.
  • Aqueous sodium carbonate solution was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature.
  • Tetrahydrofuran (900 ml) and ethyl acetate (900 ml) were . added to the reaction mixture at 25-30°C and stirred for 1 0 minutes at the same temperature.
  • Example-4 Preparation of crystalline form-N of Cabozantinib hydrochloride salt (Formula-lb):
  • Aqueous hydrochloric acid solution was added to N- ⁇ 4-[(6,7-dimethoxyquinolin-4-yl oxy]phenyl ⁇ -N'-(4-fluorophenyl)cyclopropane- l , l -dicarboxamide compound of formula- 1 (163 gm) at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and ethyl acetate, To the obtained compound, isopropanol (2.2 Its) was added at 25-30°C and stirred for 5 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound.
  • Tetrahydrofuran ( 1080 ml) and ethyl acetate (720 ml) were added to N- ⁇ 4-[(6,7- dimethoxyquinolin-4-yloxy]phenyl ⁇ -N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide ( 150 gms) at 25-30°C.
  • Aqueous hydrochloric acid (67.5 ml of hydrochloric acid in 900 ml of water) was added to the reaction mixture at 25-30 C and stirred for 3 hours at the same temperature. Filtered the reaction mixture and washed with a mixture of ethyl acetate and tetrahydrofuran.
  • Example-6 Preparation of crystalline form-M of Cabozantinib (S)-malate:
  • Example-7 Preparation of crystalline form-M of Cabozantinib (S)-malate:
  • Examplc-8 Preparation of crystalline form-M of Cabozantinib (S)-malate: A mixture of n-heptane (20 ml) and N- ⁇ 4-[(6,7-dimethoxyquinolin-4-yloxy]phenyl ⁇ - N'-(4-fluorophenyl) cyclopropane- 1 , 1 -dicarboxamide (2 gms) was stirred for 1 0 minutes at 25-30°C. Heated the reaction mixture to 70-75°C. L-malic acid (0.64 gms) was added to the reaction mixture at 70-75°C and stirred for 60 minutes at the same temperature.
  • Example-9 Preparation of crystalline form-M of Cabozantinib (S)-malate:
  • Example-10 Preparation of crystalline form-M of Cabozantinib (S)-malate:
  • Example-11 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Tetrahydrofuran (500 ml) and water (50 ml) were added to N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyI)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide (S)-malate (50 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60°C and stirred for 1 5 minutes at the same temperature. The obtained clear solution was slowly added to pre-cooled dichloromethane (1000 ml) at 0-5°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 43.0 gms.
  • Example-12 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Tetrahydrofuran (500 ml) and water (50 ml) were added to crystalline form-M of N- (4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-l ,1 - dicarboxamide (S)-malate (50 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture to through hyflow bed. The obtained particle free clear solution was slowly added to pre-cooled dichloromethane (1000 ml) at 0-5°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 39.9 gms.
  • Example-13 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Aqueous sodium carbonate solution was added to a. mixture of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-l ,1 -dicarboxamide hydrochloride (10 gms) and water (70 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Ethyl acetate (75 ml) and tetrahydrofuran (75 ml) were added to the reaction mixture at 25- 30°C and stirred for 10 minutes at the same temperature.
  • Example-14 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Aqueous sodium carbonate solution was added to a mixture of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide hydrochloride (10 gms) and water (70 ml) at 25-30°C and stirred for 10 minutes at. the same temperature.
  • Ethyl acetate (75 ml) and tetrahydrofuran (75 ml) were added to the reaction mixture at 25- 30°C and stirred for 10 minutes at the same temperature.
  • Example-15 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Aqueous sodium carbonate solution was added to a mixture of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 ,1 -dicarboxamide hydrochloride (50 gms) and water (350 ml) at 25-30°C and stirred for 10 minutes at the same temperature.
  • Ethyl acetate (375 ml) and tetrahydrofuran (375 ml) were added to the reaction mixture at 25- 30°C and stirred for 10 minutes at the same temperature.
  • Example-16 Preparation of crystalline form-S of Cabozantinib (S)-malate:
  • Aqueous sodium carbonate solution was added to a mixture of N-(4-(6,7-dimethoxy quinolin-4-y loxy)pheny t)-N' -(4-fluoropheny l)cyclopropane- 1 , 1 -dicarboxamide h drochloride (50 gms) and water (350 ml) at 25-30°C and stirred for 10 minutes at the same temperature-.
  • Ethyl acetate (375 ml) and tetrahydrofuran (375 ml) were added to the reaction mixture at 25- 30°C and stirred for 10 minutes at the same temperature.
  • Example-17 Preparation of Cabozantinib hydrochloride salt (Formula-l b):
  • the obtained compound was micronized using conventional techniques to get the desired particle size.
  • Methyl isobutyl ketone 200 Its was added to the micronized compound at 25-30°C and stirred form 3 hours at the same temperature. Filtered the compound and washed with methyl isobutyl ketone and dried to get title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un composé de N-(4-(6,7-diméthoxy quinolin-4-yloxy)phényl)-N' -( 4-fluorophényl)cyclopropane-1, 1-dicarboxamide (S)-malate de formule -1a et ses polymorphes, représenté par la structure suivante.
PCT/IN2017/000139 2016-12-07 2017-12-06 Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes WO2018104954A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP17878899.8A EP3551612A4 (fr) 2016-12-07 2017-12-06 Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes
US16/467,853 US11261160B2 (en) 2016-12-07 2017-12-06 Process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (2S)-hydroxybutanedioate and its polymorphs thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201641041767 2016-12-07
IN201641041767 2016-12-07
IN201741020998 2017-06-15
IN201741020998 2017-06-15

Publications (1)

Publication Number Publication Date
WO2018104954A1 true WO2018104954A1 (fr) 2018-06-14

Family

ID=62490925

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2017/000139 WO2018104954A1 (fr) 2016-12-07 2017-12-06 Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes

Country Status (3)

Country Link
US (1) US11261160B2 (fr)
EP (1) EP3551612A4 (fr)
WO (1) WO2018104954A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020075196A1 (fr) 2018-10-11 2020-04-16 Cipla Limited Polymorphes de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (s)-malate, leurs procédés de production et leurs utilisations pharmaceutiques
WO2021209940A1 (fr) * 2020-04-14 2021-10-21 Msn Laboratories Private Limited, R&D Center Composition pharmaceutique contenant du n-(4- (6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl) cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate
IT202000027678A1 (it) 2020-11-18 2022-05-18 Indena Spa Dispersioni solide amorfe di cabozantinib-(s)-malato e processi per la loro preparazione
US11814356B1 (en) 2023-03-29 2023-11-14 Apotex Inc. Salt of cabozantinib

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK3630726T3 (da) * 2017-05-26 2022-03-07 Exelixis Inc Krystallinske faste former af salte af n-{4-[(6,7-dimethoxyquinolin-4-yl) oxy]phenyl}-n'-(4-fluorphenyl) cyclopropan-1,1-dicarboxamid, processer til fremstilling og fremgangsmåder til anvendelse
US11649246B2 (en) * 2017-11-30 2023-05-16 Hanmi Pharm. Co., Ltd. Salts of 4-amino-N-(l-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-D]pyrimidine-7-carboxamide, and crystalline forms thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177758A1 (fr) * 2014-05-23 2015-11-26 Mylan Laboratories Ltd Nouveaux polymorphes de (s)-malate de cabozantinib et cabozantinib sous forme de base libre

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190042768A (ko) * 2010-07-16 2019-04-24 엑셀리시스, 인코포레이티드 C-met 조절제 약제학적 조성물
CN104649969B (zh) * 2013-11-22 2019-02-12 广东东阳光药业有限公司 一种替尼类药物的盐及其制备方法
WO2015123639A1 (fr) * 2014-02-14 2015-08-20 Exelixis, Inc. Formes solides cristallines du n-{4-[(6,7-diméthoxyquinolin-4-yl)oxy]phényl}-n'-(4-fluorophényl)cyclopropane-1,1-dicarboxamide, procédés de préparation, et méthodes d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015177758A1 (fr) * 2014-05-23 2015-11-26 Mylan Laboratories Ltd Nouveaux polymorphes de (s)-malate de cabozantinib et cabozantinib sous forme de base libre

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3551612A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020075196A1 (fr) 2018-10-11 2020-04-16 Cipla Limited Polymorphes de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (s)-malate, leurs procédés de production et leurs utilisations pharmaceutiques
WO2021209940A1 (fr) * 2020-04-14 2021-10-21 Msn Laboratories Private Limited, R&D Center Composition pharmaceutique contenant du n-(4- (6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl) cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate
IT202000027678A1 (it) 2020-11-18 2022-05-18 Indena Spa Dispersioni solide amorfe di cabozantinib-(s)-malato e processi per la loro preparazione
US11814356B1 (en) 2023-03-29 2023-11-14 Apotex Inc. Salt of cabozantinib

Also Published As

Publication number Publication date
EP3551612A1 (fr) 2019-10-16
EP3551612A4 (fr) 2020-08-12
US11261160B2 (en) 2022-03-01
US20210403431A1 (en) 2021-12-30

Similar Documents

Publication Publication Date Title
EP3551612A1 (fr) Procédé de préparation de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (2s)-hydroxybutanedioate et ses polymorphes
US9440979B2 (en) Process for the preparation of pralatrexate
WO2014125506A2 (fr) Procédé de préparation d'ivacaftor et de ses intermédiaires
JP2015522037A (ja) ベムラフェニブコリン塩の固体形態
US10301302B2 (en) Crystalline forms of N-(2-chloro-6-methy]phenvn-2-[F6-[4-(2-hvdroxvethvl)-L-piperazin-vil-2-methvil-4-pvrimidinvllaminol-5-thiazolecarboxamide and their process thereof
RU2736722C2 (ru) Способ получения соединения пиразоламида
WO2019167085A1 (fr) Procédé de préparation de méthanesulfonate de (s)-2-[[4-[(3-fluorophényl)méthoxy]phényl]méthyl]amino propanamide
US11236050B2 (en) Polymorphs of 4-[3-chloro-4-(n′-cyclopropyl ureido)phenoxy] -7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
US9580414B2 (en) Salts and hydrates of antipsychotics
WO2015087343A2 (fr) Procédé amélioré pour la préparation de nilotinib et de sels pharmaceutiquement acceptables de celui-ci
US10144710B2 (en) Process for the preparation of 4-[-({[4-choloro-3(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide and its polymorphs thereof
WO2017163258A1 (fr) Procédé de préparation de n-[6-(cis-2,6-diméthylmorpholin-4-yl)pyridine-3-yl]-2- méthyl-4'-(trifluorométhoxy) [1,1'-biphényl]-3-carboxamide et de ses polymorphes
WO2014188445A1 (fr) PROCÉDÉ DE PRÉPARATION DE L'ACÉTATE DE (3β)-17-(3-PYRIDINYL)ANDROSTA-5,16-DIÈNE-3-YLE ET D'UN POLYMORPHE DE CELUI-CI
US11498902B2 (en) Process for the preparation of Cabozantinib and its pharmaceutically acceptable salts thereof
WO2020225831A1 (fr) Procédé amélioré pour la préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl] imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide
WO2022215083A1 (fr) Formes à l'état solide de (s)-quinuclidin-3-yl (2-(2-(4-fluorophényl)thiazol-4-yl)propan-2-yl) carbamate ou de sels et procédé de préparation associé
CA2828423A1 (fr) Derives de 3-ureidoisoquinolein-8-yle
US8629166B2 (en) 5-cycloalkyl- or 5-heterocyclyl-nicotinamides
JPH04330060A (ja) ピリジン−２，４−および−２，５−ジカルボン酸のジ（ニトロキシアルキル）アミド、その製造方法およびその使用
Rajan et al. Process For The Preparation of N-(5-chloropyridin-2-yl)-2 [4-(N, N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide And Its Pharmaceutically Acceptable Salts
CA3213086A1 (fr) Procede de preparation de cabozantinib
WO2024111001A1 (fr) Formes cristallines de fumarate de n-(4-(6,7-diméthoxyquinoléin-4-yloxy)phényl)-n'-(4-fluorophényl)cyclopropane-1,1-dicarboxamide et leur procédé de préparation
EP2621899B1 (fr) Nouveaux dérivés de méthylcyclohexane et leurs utilisations
JP2021161097A (ja) テネリグリプチンの新規結晶形及びその製造方法
US20230045450A1 (en) Process for preparing aficamten

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17878899

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017878899

Country of ref document: EP

Effective date: 20190708